rs764896402

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_133510.4(RAD51B):c.84G>A(p.Gln28Gln) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00000962 in 1,455,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RAD51B
NM_133510.4 splice_region, synonymous

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 4.27

Publications

3 publications found

Variant links:

Genes affected

RAD51B (HGNC:9822): (RAD51 paralog B) The protein encoded by this gene is a member of the RAD51 protein family. RAD51 family members are evolutionarily conserved proteins essential for DNA repair by homologous recombination. This protein has been shown to form a stable heterodimer with the family member RAD51C, which further interacts with the other family members, such as RAD51, XRCC2, and XRCC3. Overexpression of this gene was found to cause cell cycle G1 delay and cell apoptosis, which suggested a role of this protein in sensing DNA damage. Rearrangements between this locus and high mobility group AT-hook 2 (HMGA2, GeneID 8091) have been observed in uterine leiomyomata. [provided by RefSeq, Mar 2016]

RAD51B Gene-Disease associations (from GenCC):

primary ovarian failure
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

RAD51B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 14-67823627-G-A is Pathogenic according to our data. Variant chr14-67823627-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 221910.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51B	NM_133510.4 link	c.84G>A	p.Gln28Gln	splice_region_variant, synonymous_variant	Exon 2 of 11	ENST00000471583.6	NP_598194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51B	ENST00000471583.6 link	c.84G>A	p.Gln28Gln	splice_region_variant, synonymous_variant	Exon 2 of 11	1	NM_133510.4	ENSP00000418859.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151906

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000403

AC:

AN:

248200

AF XY:

0.00000746

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000962

AC:

AN:

1455598

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

724074

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33240

American (AMR)

AF:

0.00

AC:

AN:

44058

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25986

East Asian (EAS)

AF:

0.00

AC:

AN:

39518

South Asian (SAS)

AF:

0.00

AC:

AN:

84982

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1108636

Other (OTH)

AF:

0.00

AC:

AN:

60142

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

151906

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74170

African (AFR)

AF:

0.00

AC:

AN:

41306

American (AMR)

AF:

0.00

AC:

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10566

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2088

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary breast ovarian cancer syndrome

Pathogenic:2

Dec 12, 2015

Clinical Cancer Genetics and Family Consultants, Athens Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The mutation was observed in one patient with high grade DCIS, Her2 positive and strong family history (mother with bilateral breast cancer and maternal aunt with breast cancer and thyroid cancer). The same mutation has been described as a leaky splicing variant of the RAD51B (PMID:26898890). First time in Greece, it has been observed among 164 patients with breast and ovarian cancers tested in the our clinic. We consider this variant to be likely pathogenic. -

Dec 22, 2015

Dr. Peter K. Rogan Lab, Western University

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Sequenced patient with familial breast cancer -

not provided

Pathogenic:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Jan 01, 2020

GeneKor MSA

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is change of the last base in exon 2 of the RAD51B gene, which is conserved in the human genome and other genomes. Although it does not lead to an amino acid change, it is expected that this alteration causes improper sRNA splicing and deletion of the entire exon. Thus the protein produced by one allele is expected to be truncated and non-functional. This variant has been described in the international literature in individuals undergoing panel testing for hereditary syndrome (PMID: 31159747). The mutation database ClinVar contains entries for this variant (Variation ID: 221910). -

not specified

Uncertain:1

Apr 01, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.84G>A variant (also known as p.Q28Q), located in coding exon 1 of the RAD51B gene, results from a G to A substitution at nucleotide position 84. This nucleotide substitution does not change the glutamine at codon 28. However, this change occurs in the last base pair of coding exon 1, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

4.3

PromoterAI

-0.050

Neutral

(source)

Mutation Taster

=30/70

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.84

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.84

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over